14alpha,15alpha-ketonides of alkyl 3-oxygenated-14alpha,15alpha-dihydroxy -4,17(20)-cis-pregnadien-21-oates,derivatives thereof,and intermediates and processes therefor



United States Patent 3,502,659 14a,15a-KETONIDES 0F ALKYL 3-OXYGENATED- l4a,15a-DIHYDROXY-4,l7(20)-ClS-PREGNADIEN- 2l-0ATES, DERIVATIVES THEREOF, AND IN- TERMEDIATES AND PROCESSES THEREFOR Philip F. Beal III, Kalamazoo, and Robert W. Jackson, Portage, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed Apr. 3, 1967, Ser. No. 627,658 Int. Cl. C07c 173/00, 169/00 US. Cl. 260239.55 24 Claims ABSTRACT OF THE DISCLOSURE This invention relates to novel steroid compounds and processes for their preparation; more particularly to those compounds embraced by the formula COOR' wherein the l(2)-and 6(7)-carbon atom linkages are selected from the group consisting of single bonds and double bonds; R and R are selected from the group consisting of hydrogen and lower alkyl; Z is selected from the group consisting of the methylene radical CH the fi-hydroxymethylene radical and the carbonyl radical @O); a and b are selected from the group consisting of lower alkyl of from one through twelve carbon atoms, phenyl and benzyl. The compounds of the invention possess anti-inflammatory, anti-viral, anti-microbial, and antihormonal activities.

BRIEF SUMMARY OF INVENTION The novel compounds of this invention and processes for their production are illustratively represented by the following sequence of formulae:

Patented Mar. 24, 1970 CH3 on,

on, CH3 4; 0:0 =0 0H, 1 CH3 1 L --0o0R' 1 IV R III on, on,

00K COOR CH 22H OH; H on,

/ I am on R v R vr tyvn CH3 CH3 000R 000R 5 (3H CH: II VI I Vii H3O /2 g l g o o o 0 o: 0 0: o i a b l a b R R on, on,

coon 000R bit on CH3 Z/\ H() E30 /1\/ 5 2 l l a y 2 a a 0 7 o o: 7 o

i a b l a b R R IX X wherein Z is selected from the group consisting of the methylene and carbonyl radicals and 1(2), 6(7), a, b R and R have the same meaning as above.

The novel compounds embraced by Formulae V through X of the flow-sheet, above, are prepared :by the route shown therein, employing the methods and reactions described below.

(1) The first step of the process involves the hydroxylation of the known compounds of Formula I in accordance with the procedure disclosed Preparation 1 of US. Patent 3,05 3,854, namely by fermenting a compound of the progesterone series, e.g., a A*-3,20-dione (or 3,11,20-tn'one) (I) with the spores of Penicillium urticae ATCC 10120 in a nutrient medium to yield a corresponding 15a-hydroxy compound, e.g., a 15a-hydroxy-A -3,2O- dione (or 3,1l,20-trione) (II).

(2) Treatment of a thus produced compound of Formula II with an alkylhaloformate (e.g., methylchloro= formate) at low temperatures (e.g., between about 20 C. to about +20 C.) yields a corresponding l5a-alkyl carbonate, e.g., a 15a-hydroxy-A -3,20-dione (or 3,11,20- trione), 15-alkyl carbonate (III).

(3) Pyrolysis of a compound of Formula III (advantageously under vacuum at temperatures between about 200 to about 300 C.) results in its loss of CO and alkyl OH at the lint-position to yield a corresponding 4,14- pregnadiene-3,20-dione (or 3,11,20-trione) (IV).

(4) A compound of Formula IV is subjected to Favorskii rearrangement in accordance with the method described in J. Amer. Chem. Soc 77, 4438 to yield a corresponding alkyl, 3-keto (or 3,1l-diketo)-4,14,17(2G)-cispregnatrien-Zl-oate (V).

(5) Treatment of a thus produced compound of Formula V at moderaate (room) temperature with an oxidant, such as osmium tetroxide dissolved in an organic solvent such as ether, or potassium permanganate weak acid solution (e.g., formic acid or acetic acid), yields a corresponding alkyl 3-keto (or 3,11-(llk8t0)l4oc,l5a-dlhydroxy-4, l 7 20) -cis-pregnadien-2 l -oate (VI) (6) A compound of Formula VI on treatment in the manner described in J. Amer. Chem. Soc. 80, 2338, namely, at moderate (room) temperature with an aliphatic ketone (e.g., acetone diethyl ketone, dibutyl ke tone, ethyloctyl ketone, 3,3-dimethyl-2-butanone, etc.) or an aromatic ketone (e.g., acetophenone, propiophenone, butyrophenone, isocaprophenone, l-phenyl-Z-propanone, l-phenyl-3-butanone, l-phenyl-4-pentanone, 1,3-diphenyl- Z-propanone, dibenZyl ketone, methyl p-tolyl ketone, etc.) in the presence of an acid catalyst e.g., perchloric acid, p-toluenesulfonic acid, hydrochloric auid, etc.), yields a corresponding alkyl 3-keto (or 3,1ldiketo)-l4u,l5m-dihydroxy-4, 17 (29) -cis-pregnadien-2l-oate, 14a, 1 5a-k6tOnld6 (VII).

(7) Reduction of a compound of Formula VII, Wherein Z is carbonyl, e.g., with an alkali metal borohydride such as sodium borohydride, yields a corresponding alkyl, 318,11B,l4a,15atetrahydroxy-4,17(20) cis pregnadien- 2l-oate,l4a,l5e ketonide (VII).

(8) Oxidation of the 3 3-hydroxy group of a compound of Formula VII by methods well known in the steroid art, e.g., by treatment with manganese dioxide at room temperature in a solvent such as ethyl acetate, chloroform and the like (in the manner disclosed in J. Org. Chem. 19, 1509 and J. Amer. Chem. Soc. 75, 5930') yields a corresponding alkyl 3-keto-1lfi,14a,l5a-t1ihydroxy-4,17(20)- cis-pregnadien-2l-oate,14a,15a-ketonide (VIII).

(9) The novel compounds of Formulae VII and VIII are converted to their A A and A -counterparts in accordance with procedures well known in the art. The A -derivatives (IX and X) of Formulae VII and VIII, respectively, are produced by 1,2-dehydrogenation with selenium dioxide in the manner disclosed in US. Patent 2,971,886 and by dicyanodichlorobenzoquinone (DDQ) as in British Patent 852,847; e.g., by these procedures an alkyl 3,1 1-diketo14u,15a-dihydroxy-4, 17 (20 -cis-pregnadien-2l-oate, 140:,15oc-k6tGI1ld6 (VII) and the corresponding llfi-hydroxy compound (VIII) are converted to their respective 1,4,l7(20)-cis-pregnatrienes (IX and X). The M-compounds embraced by Formulae VII and VIII when reacted with tetrachloro-p-benzoquinone (chloranil) in the manner described in J. Amer. Chem. Soc. 79, l257, yield their corresponding A -derivatives, e.g., alkyl 3,El-diketo-l4a,l5a-dihydroxy 4,6,l7(g0)-cispregnatrien-Zl-oate, 14a,15a-kgonide FIX) and alkyl 3-keto-1lB,l4a,l5a-trihydroxy 4,6,17(2-0) cis pregnatrien-Zl-oate, l4a,l5a-ketonide (X). The M' -compounds (IX and X) can be dehydrogenated at the 1(2)-position with selenium dioxide to give the corresponding A compounds, e.g., alkyl 3-ket0-14a,15a-dlhYdIOXY-1,4,6, 17(20)-cis-pregnatetraen-2l-oate, 14a,15a-ketonide (IX) and alkyl 3-keto-116,140,1Su-trihydroXy-1,4,6,17(20)-cispregnatetraen-Zl-oate, l4a,l5a-keto nide (X). The [3 compounds (IX and X) can preferably be prepared by the 6-dehydrogenation of the corresponding A -compounds (IX and X) by reaction with chloranil. The A compounds (IX and X) can also be prepared directly from the M-compounds of Formulae VII and VIII, respectively, by reaction with chloranil at elevated temperatures in accordance with the method also set forth in J. Amer. Chem. Soc. 79, 1257.

The 2l-oic acid alkyl esters embraced by Formulae V through X can be converted to their corresponding 2l-oic acids (V' through X) by hydrolysis, e.g., as in Example 1 of US. Patent 3,162,63l.

All of the compounds included within Formulae. II through X of the flow-sheet, above, can be isolated from their respective reaction mixtures by conventional means, for example, when a water-miscible solvent is used, by pouring the reaction mixture into water and separating the resulting precipitate by filtration or by extraction with water-immiscible solvents. Additional purification of the products can be accomplished by conventional means, for example, by elution chromatography from an adsorbent column with a suitable solvent such as acetone, methanol, dilute methanol, ethanol, ether, methylene chloride and Skellysolve B (hexanes), mixtures and combinations of these solvents; also by gradient elution chromatography from an adsorbent column with a suitable mixture of solvents, such as, methylene chloride-Skellysolve B, acetone-Skellysolve B, and the like.

The compounds embraced by Formulae II through X possess anti-inflammatory, anti-viral, anti-microbial and anti-hormonal activities. They stimulate natural host-defense mechanisms to infectious diseases and virus induced processes. They antogonize the action of prostaglandins and also of Slow Reacting Substance (SRS-A), which is released during anaphylaxis, and are consequently useful in protection against allergy, anaphylaxis, emphysema and hay fever, as well as in the treatment of these ailments in medical and veterinary practice. The anti-SRS-A activity of the aforesaid compounds is assayed by The Protection of Sensitized Guinea Pigs Against Collapse From Antigen Containing Aerosol Test, a modification of the method described by W. G. Smith, J. Pharm. and Pharmacol. 13, l( 1961).

The compounds of the invention can be prepared and administered to mammals, birds, humans, and animals, in a wide variety of oral or parenteral dosage forms, singly or in admixture with other coacting compounds. They can be administered with a pharmaceutical carrier which can be a solid material or a liquid in which the compound is dissolved, dispersed or suspended. The solid compositions can take the form of tablets, powders, capsules, pills, or the like, preferably in unit dosage forms for simple administration or precise dosages. The liquid compositions can take the form of solutions, emulsions, suspensions, syrups, or elixirs.

DETAILED DESCRlPTION adjusted to a pH between 5.5 and 6. Twelve liters of this sterilized medium was inoculated with spores of Penicillium urticae ATCC 10120 andincubated for aperiod of 24 hours at a temperatureof 26 C., while stirring and aerating at the rate of 20 to 100 ml. of air per minute per liter of medium. To this medium containing a 24 hour growth of Penicilliuml urticae was added 2 g'Iof 11-ketoprogesterone (I), dissolved in 100* ml. of acetone. After an'additional 24 hour period of incubation under the same conditions of temperature and aeration, the beer and mycelium were separated. The rriycelium was filtered, Washed twice, each time with a volume of acetone approximately equal to the volume of the mycelium, and extracted twice, each time with a volume of methylene chloride approximately equal to the volume of the mycelium. The acetone and methylene chloride extracts, including solvent, were added to the beer filtrate and the combined extracts and beer'filtrates were extracted successively with two one-half by volume portions of methylene chloride and then with two one-fourth by volume portions of methylene chloride. The methylenechloride extracts were washed with two one-tenth by volume portions of a 2% aqueous solution of sodium bicarbonate and then with two one-tenth by volume portions of water. After drying the methylene chloride extracts with about 3 to 5 g. of anhydrous sodium sulfate per liter of solvent and filtering, the solvent was distilled from the filtrate. The residue thus obtained was recrystallized two times from acetone and ether in 1 to 1 ratio and one time from acetone and Skellysolve B to give 15a-hydroxy-11-ketoprogesterone '(II) of melting point 227 to 229 (in EtOH).

Following the procedure of Preparation 1 but substituting for ll-ketoprogester one (I) the following:

(1) progesterone (I), (2) 6ot-methylprogesterone (I).;and x (3 6u-methyl-1 l-ketoprogesterone (I),

yields, respectively,

(1) 15ot-hydroxyprogesterone (II), (2) 15u-hydroxy-6ot-methylprogesterone (II) and (3) 15a-hydroxy-6a-methyl-1l-ketoprogesterone (II).

Example 1 .-15a-hydroxy-4-pregnene-3, 1 1,20- trione-15-methyl carbonate (III) A solution of 18 g. of 15a-hydroxy-4-pregnene-3,11,20- trione (II) in 120 ml. of pyridine was cooled in an icesalt bath to 0 C. This solution was treated with 18 ml. of methyl chloroformate under anhydrous conditions by dropwise addition of the latter over a period of about 30 minutes, so that the temperature of the reaction mixture did not rise above 3 C. The reaction mixture was kept in a refrigerator at between about 8 to about 10 C. for about hours. The mixture was again cooled to 0 C. with an ice-salt bath and 200 ml. of water added slowly so that the temperature of the'rnixture did not exceed 10 C. The mixturewas stirred in an ice bath for about 2 hours and filtered on a sintered glass Buchner funnel by suction. The crystalline product was washed thoroughly with water and dried in vacuo at 40 C. to constant weight. The yield of 15a-hydroxy-4-pregnene-3,11,20-trione, 15- methyl carbonate (III) was 13.85 g. and the compound had a melting point of 203 to 206 C.

AnaIysis.-Calcd. for C H O (percent): C, 68.63; H, 7.51. Found (percent): C, 68.36; H, 7.31.

Following the procedure of Example 1 but substituting other alkyl haloformates for methyl chloroformate, e.g., ethyl fluoroformate, propyl bromoformate, etc., yields the corresponding alkyl carbonate esters, namely, 15oz hydroxy-4-pregnene-3,11,20-trione, 15-ethyl carbonate, 15ozhydroxy 4-pregnene-3,11,20-trione, 15-propyl carbonate, etc.

Following the procedure of the immediately preceding paragraph and of Example 1 but'substitilting such starting materials and alkyl haloformates as the following:

yields, respectively,

(1) 15a-hydroxyprogesterone, 15-butyl carbonate (III), (2) 15a hydroxy 6ot-methyl-1l-ketoprogesterone, 15-

ethyl carbonate (III), etc.

Example 2.-4,14-pregnadiene-3,11,20-trione (IV) 29 g. of hydroxy-4-pregnene-3,11,20-trione, 15- methyl carbonate (III) was pyrolyzed in approximately 5 g. increments as follows: the aforesaid compound (III) was charged into a 250 ml. round bottom flask equipped with a magnetic stirring bar and an adapter for evacuating the flask, which then was half immersed in a bath of Woods Metal (50% bismuth, 25% lead, 12.5% tin and 12.5% cadmium) and placed on a magnetic stirring device. The material was pyrolyzed for about 10 minutes at a temperature of between about 240 to about 280 C. The cooled crude products were combined and chromatographed over 750 g. of Florisil (synthe tic magnesium silicate). The column was developed with ten 500 ml. portions of 15% acetone in Skellysolver B and six 500 ml. portions of 25% acetone inSkellysolve B. Fractions 6 through 9 gave 17.8 g. of crude product (IV), which on recrystallization from methanol yielded 2 crops weighing 12.1 g. melting at 183 to 184 C. Fractions 10 through 16 gave 7.23 g. of starting material (III). An analytical sample of the product 4,14-pregnadiene-3,11,20-trione (IV), melted at to 198 C.; [a] +219 (chloroform); A max. 237 ma; 6: 16,700 (ethanol).

Analysis.Calcd. for C H- gO (percent): C, 77.26; H, 8.03. Found (percent): C, 76.92; H, 7.83.

Following the procedure of Example 2 but substituting for 150s hydroxy 4-pregnene-3,11,20-trione, 15-methyl carbonate (III) other compounds such as:

(1) 15a hydroxy-6a-methylprogesterone, 15-propyl carbonate (III),

(2) 15a-hydroxy-6a-methyl-1l-ketoprogesterone, 15-ethyl carbonate, etc.,

yields, respectively,

( 1) 6ot-methyl-4,14-pregnadiene-3,20-dione (IV), (2) 6oz methyl-4,14-pregnadiene-3,11,20-trione (IV),

etc.

Example 3.Methyl 3,11-diketo-4,14,17(20)-cis-pregnatrien-21-oate (V) The aforesaid compound (V) and its 21-hydrogen counterpart (Va), as well as their corresponding a-methyl and ll-hydrogen derivatives, are, prepared from their respective precursors of Formula IV by subjecting the appropriate starting material (IV) to Favorskii rearrangement in accordance with the method described" in U.S. Patent 2,790,814, illustratively represented by the following reaction sequence:

CH3 ONa CH: o 0 02m 1 [1:0 CH3 I o 0 0 02115 NaO C- IVa CH; 0H

=0 CH3 l To 0 02H. HO 0= [Vb if BrzC1CCOC2H 0:0 CH3 H30 Br IVc 0000113 5H CH3 Br IVd wherein R and Z have the same meaning as above.

In a l l. flask equipped with a stirrer, nitrogen inlet tube, dropping funnel and protected from atmospheric moisture with a desiccant tube of anhydrous calcium sulfate (Drierite), 18.2 g. of 4,14 pregnadiene-3,11,20-trione (IV) was dissolved in 275 ml. of t-butyl alcohol. The mixture was warmed on a steam bath to dissolve the steroid. When its temperature was approximately 55 C., 30 ml. of diethyl oxalate and 30 ml. of 25% sodium methoxide in methanol was added. The reaction mixture was stirred for about 15 minutes and allowed to cool to about 30 C. The flask was then immersed in an ice-salt bath and a solution (precooled to 5 C.) containing 6.8 g. of sodium acetate and 8.1 ml. of acetic acid in 450 ml. of methanol added. The reaction mixture was cooled to about 0 C. and a freshly prepared solution of 28.0 g. of bromine in 270 ml. of cold (0 C.) methanol added slowly over a period of about 10 minutes. To this mixture (contained in a flask surrounded by an ice bath) 67 ml. of 25% sodium methoxide in methanol was added and the mixture allowed to stand for about 3 hours; when the ice bath was removed the temperature within the flask rose to about 23 C. The mixture was then stirred with 45 ml. of acetic acid and 8.9 g. of powdered zinc for about 30 minutes. The excess zinc was filtered on a bed of diatomaceous earth (Celite) on a sintered glass Buchner funnel. The filtrate was poured into 4 l. of ice and water and the crude product precipitated. This material was collected by filtration and taken up in methylene chloride. This solution was dried over anhydrous sodium sulfate and the crude product purified by chromatography over 750 ml. of Florisil. A peak of 9 fractions eluted with 400 ml. portions of a mixture of 12.5% acetone and 87.5% Skellysolve B gave 10.8 g. of product (V). This material was recrystallized from acetone-Skellysolve B to give 8.5 g. of methyl 3,11 diketo-4,14,17(20)-cis-pregnatrien-21- oate (V) having a melting point of 208 to 214 C., A max. 237 m 6 20, 750/ethanol.

Analysis.Calcd. for C H O (percent): C, 74.54; H, 7.39. Found (percent): C, 73.79; H, 7.36.

Following the procedure of Example 3 but substituting for 4.14 pregnadiene 3,11,20 trione (IV) other compounds such as:

(1) 4,14-pregnadiene-3,20-dione (1V),

9 2) 6a-methyl-4,14-pregnadiene-3,20-dione (IV), (3) 6a-methyl-4,14-pregnadiene 3,11,20 trione (IV), etc.,

yields, respectively,

Example 4.3,l1-diketo-4,14,17(20)-cis-pregnatrien- 2l-oic acid (Va) A solution of 2.5 g. of methyl 3,11-diketo-4,14,17(20)- cis-pregnatrien-Zl-oate (V) in 75 m1. of methanol is refluxed under a nitrogen atmosphere for about 20 hours with a solution of 2.5 g. of potassium hydroxide in 15 ml. of water. The mixture is then diluted with 200 ml. of water and extracted with methylene chloride to remove any unhydrolyzed ester (V). The aqueous mixture is made acid with ice cold dilute hydrochloric acid. The steroid is extracted with methylene chloride and the ex tract washed with water until the washings become neutral to test paper. The extract is dried over anhydrous sodium sulfate and concentrated to dryness by distillation in vacuo. The residue is crystallized from ether to give pure 3,11-diketo-4,14,l7(20)-cis-pregnatrien-21-oic acid (Va).

Following the procedure of Example 4 but substituting for methyl 3,11-diketo-4,14,17(20) cis pregnatrien 21- oate (V) other compounds such as:

(1) methyl 3-keto-4,14,17(20)-cis-pregnatrien 21 oate 2) methyl 3-keto-6a-methyl-4,l4,17(20')-cis-pregnatrien- 21-oate (V),

('3) methyl 3,11-diketo-6a-methyl-4,l4,17(20)-cis pregnatrien-Zl-oate (V), etc.,

yields, respectively,

(1) 3-keto-4,14,17(20)-cis-pregnatrien-21-oic acid (Va),

(2) 3-keto- 6a-methyl-4,14,17(20)-cis-pregnatrien-2l oic acid (Va).

(3) 3,11-diketo-6a-methyl-4,14,l7(20)-cis pregnatrien- 21-oic acid (Va), etc.

Example .Methyl 3,1 l-diketo-14a,15a-dihydroxy- 4,17(20)-cis-pregnadien-21-oate (VI) In 35 ml. of pyridine, 2.3 g. of methyl 3,l1-diketo-4,14, 17(20)-cis-pregnatrien-2l-oate (V) Was dissolved. This solution was treated for about 1.5 hours at room temperature with a solution of 1.83 g. of osmium tetroxide in 137 ml. of ether. The reaction mixture was then treated for about 30 minutes with 350 ml. of 0.5% sodium hydrosulfite solution. The ether and most of the pyridine was removed by vacuum distillation from a steam bath. The aqueous residue was extracted several times with methylene chloride. The extract was dried over anhydrous sodium sulfate and concentrated to dryness by vacuum distillation to remove the last traces of pyridine. The nearly black residue weighing about 2.2 g. was redissolved in methylene chloride and chromatographed over a 100 g. column of Florisil. A peak of 7 fractions eluted with 15% acetone in Skellysolve B gave 0.35 g. of starting material (V); a peak of 11 fractions eluted with 25% acetone in Skellysolve B gave 0.445 of product (VI) which Was recrystallized from the same solvent pair to give 0.43 g. of methyl 3,1l-diketo-l4a,15a-dihydroxy 4,17(20 cispregnadien-Zl-oate (VI) having a melting point of 252 to 253 C., A max. 236, e=25,700.

Analysis.Calcd. for C H O (percent): C, 68.02; H, 7.26. Found (percent): C, 67.83; H, 7.28.

Following the procedure of Example 5 but substituting for methyl 3,11-diketo-4,14,17 (20) cis pregnatrien 21- oate (V) other compounds such as:

10 (1) methyl 3-keto-4,14,17(20)-cis-pregnatrien 21 oate (2) methyl 3-keto-6a-methyl-4,l4,17(20)-cis-pregnatrien- 21-oate (V), (3) methyl 3,11-diketo-6u-methyl-4,14,17(20) cis pregnatrien-Zl-oate (V), etc.,

yields respectively,

(1) methyl 3-keto-14a,15a-dihydr0xy-4,17(20)-cis pregnadien-21-oate (VI),

(2) methyl 3-keto-14a,15a-dihydroxy 6a methyl 4,17

(20) -cis-pregnadien-2 l-oate (VI),

(3) methyl 3,11-diketo-14a,l5a-dihydroxy-6a-methyl 4,

17(20)-cis-pregnadien-21-oate (VI), etc.

Example 6.3,11-diketo-14a,l5a-dihydroxy-4,l7(20)- cis-pregnadien-Zl-oic acid (VIa) Following the procedure of Example 4 but substituting methyl 3,11-diketo-14a,15a-dihydroxy-4,17(20)-cis pregnadien-Zl-oate (VI) as starting material, yields 3,11- diketo-14a,l5a-dihydroxy-4,17(20)-cis-pregnadien-21 oic acid (VIa).

Following the procedure of Example 6 but substituting for methyl 3,11-diketo-14a,ISa-dihydroxy 4,17(20) cispregnadien-Zl-oate (VI) other compounds such as:

(1 methyl 3-keto- 14a, 1 5a-dihydroxy-4, 17 (20 -cis-pregnadien-Zl-oate (VI),

(2) methyl 3-keto-14a,15a-dihydroxy-6a methyl 4,17

(20)-cis-pregnadien-21-oate (VI),

(3 methyl 3, l 1-diketo-l4a, 15 a-dihydrOXy-Sa-methyl 4,

17 20) -cis-pregnadien-2 l-oate (VI), etc.,

yields, respectively,

( 1) 3-keto-14a,15a-dihydroxy-4,17(20) cis pregnadien- 21-oic acid (VIa),

(2) 3-keto-14a,15a-dihydroxy-6a-methy1 4,17(20) cispregnadien-Zl-oic acid (VIa), etc.

Example 7.Methyl 3,1l-diketo-14a,15a-dihydroxy-4,17 (20)-cis-pregnadien-21-oate, 14a,l5a-acetonide (VII) 2.05 g. of methyl 3,11-diketo-14a,15a-dihydroxy-4,17 (20)-cis-pregnadien-2l-oate (VI) was dissolved in ml. of acetone and treated with 10 drops of 70% perchloric acid for about 20 minutes at room temperature. The excess acid was neutralized by pouring the mixture into a mixture of sodium bicarbonate solution and ice water. The reaction mixture was extracted with methylene chloride and the extract dried over anhydrous sodium sulfate and concentrated to dryness by vacuum distillation. The residue was chromatographed over a g. column of Florisil. A peak of 7 fractions eluted with 15% acetone in Skellysolve B gave 2 g. of methyl 3,11- diketo 1401,1511: dihydroxy-4,17(20)-cis-pregnadien-21- oate, l4a,l5a-acetonide (VII) having a melting point of 169 to 172 C., A max. 233.5, e=23,850/C H OH.

Analysis.-Calcd. for C H O (percent): C, 70.07; H, 7.53. Found (percent): C, 69.10; H, 7.34.

Following the procedure of Example 7 but substituting for methyl 3,11-diketo-14u,l5a-dihydroxy-4,17(20)-cispregnadien-Zl-oate (VI) other compounds such as:

(1) methyl 3-keto-14a,15a-dihydroxy-4,17(20)-cis-pregnadien-21-oate (VI),

(2) methyl 3-keto-14a,15a-dihydroxy 6u-methyl-4,17

(20)-cis-pregnadien-2l-oate (VI), (3) methyl 3,1 1-diketo-14a,15a-dihydroxy-6u-methy1-4,17

(20)-cis-pregnadien-21-oate (VI), etc.,

yields, respectively,

(1) methyl 3-keto 14a,l5a-dihydroxy-4,17(20)-cis-pregnadien-21-oate, 14a,15a-acetonide (VII),

(2) methyl 3-ketO-14oc,15u dihydroxy 6u-methyl-4,l7

(20)-cis-pregnadien-2l-oate, 14a,15a-acetonide (VII), (3) methyl 3,11 diketo-14a,15a-dihydroxy-6u-meth'yl- 4,17(20)-cis-pregnadien-21 oate, 14a,15a acetonide (VII), etc.

Following the procedures of. the immediatelypreceding paragraph and of Example 7,, but substituting for acetone other ketones such as methyl ethyl ketone, diethyl keton e, methyl propyl ketone, 3,3-dimethyl- 2-butanone, dibutyl ketone, diheptyl ketone, ethyl octyl ketone, acetophenone, propiophenone, butyrophenone, benzophenone, l-phenyl- 2 -propanone, 1,3-diphenyl-2-propanone, 1-phenyl-3-butanone, dibenzyl ketone, etc}; yields the corresponding ketone derivatives (ketonides) of the 14a,15;o-dihydroxysteroids embraced by Formula VII of the flow-sheet, above. For example, treating methyl 3,l-(llk6lIO-I4a,l5adihydroxy 6a methyl;4,l7(20)-cis-pregnadien-2l-oate (VI) with acetophenone yields its l4a,l5u-acetophenonide (VII). H e

Example 8.3,11-diketo-14a,15a-dihydroxy-4,17 (20)- cis-pregnadien-Zl-oic acid, 14 ,15o-acetonide (VIIa) (1) methyl 3-ketc--14u,15o-dihydroxy-4,17(20)-cis-pregnadien-21-oate, 14a,15a-acetonide (VII), 1

(2) methyl 3 keto 140i,l5u-dihydroxy-6a-methyl-4,17 (20)-cis-prenadien-2l oate, 14a,l5a-acetonide (VII),

etc.,

yields, respectively, H

( 1) 3-keto-14a,15x-dihydroxy-4,17(20)-cis pregnadien- 21-oic acid, 14a,15o-acetonide (VIla);

(2) 3-keto 14a,15a-l1YCl1OXY-6ot-1Tl6lhYl 4,17(20) cispregnadien-Zl-oic acid, l4a,15a-acetor1ide (VII'zz), etc.

Following the procedures of the immediately preceding paragraph and of Example 8, but substituting another ketone for acetone, eeg, dibeniyl ketone, yields the corresponding dibenzyl ketonides (VIIa). 1

Example 9.e-Methyl 3 9,11 3,it4a,15 oz tetrahydroxy-4,17 (20)-cis-pregnadien-21-oate, 14a,l5a-3.C6lIOI1lCi (VII') ,One part of methyl 3,lfl-dlketO-l4oL,l5a;dlhydI'0XE} 4,17(20) cis pregnadien 21 oate, l4a,l5aacetonide (VII) was dissolved in 20 parts of isopropyl alcohol and refluxed with a solution of 2 parts of sodiumborohydride in 4 parts of 0.1 N sodium hydroxide for about 6 hours. ;The mixture was cooled to, about 10 C. and madejust acid to test paper with dilute (about acetic acid. The mixture was partitioned between methylene chloride and water and the organic extract dried oyer anhydrous sodium sulfate. The dried extract was concentrated to a crystalline mass by vacuum distillation from a; water bath kept at about 60 C. to yield methyl 3B,llfi,l4a,l5ottetrahydroxy-4,17(20) cis pregnadien-Zl-oate, l4ot,l5aacetonide (VII'). e 2

Following the procedure of Example 9, but substituting for methyl 3,11-diketo-14e,15a-dihydroxy-4,17(20)- cis-pregnatrien-Zl-oate, 14a,15z-acetonide (VII) a corresponding compound prepared from one of the ketones set forth in the second paragraph following Example 7, yields another 14a,15u-ketonide of methyl 18,115,140, 1565 tetralrydroxy 4,l7(20 cis pregnadien-Zl-oate (V Following the precedure of Example 9 but substituting for methyl 3,11-diketo-14e,15a-dihydroxy-4,17(20)-cispregnadien-21-oate, 140:,15E-t106t0t1ld6 (VII) its corresponding 6a-methyl compound (VII), yields methyl 3B,11p,14a,15u tetrahydroxy 611 i methyl-4,17(20)-cis pregnadien-Zl-oate, l4a,15 x-acetonide (VII').

12 Example l0.3fi,l1B,14u,15 t-tetrahydroxy-4,17(20)-cispregnadien-Zl-oie acid, 14a,l5a-acetonide (VII'a) Following the procedure of Example 4 but substituting methyl 35,11/3,140:,15a-tetrahydroxy-4,17(2O)-cis-pregnadien-Zl-oate, 14a, 15a-acetonide (VII') as starting material, yields 3B,ll, 3,l4oc,15oc:- tetrahydroxy 4,l7(20)-cispregnadien-Zl-oicacid, l4a,15a-acetonide (VIIa).

Following the procedure of Example 10 but employing methyl 35,115, 4a,15a-tetrahydroxy-6a-niethyl-4,17(20)- cis-pregiaadien-Zl-oate, l4a,15a-acetonide (VII') as' starting material, yields 36,11B,l4a,15a-tetrahydroxy-6umethyl-4,17(20) cis-pregnadien-2l-oic acid, 14a,15 x-acetonide (VIIa). I

Following the procedures of the immediately preceding paragraph and Example 10, but substituting for the l4a,l5a-acetonides (VII') employed herein as starting materials a corresponding compound prepared from one of the ketones set forth in the second paragraph following Example 7 yields'another '14u,15oc-ketOnid@ (V I'a).

Example 1 1.-Methyl 3-ket o-l 1;3,14;,15a-trihydroxy-4, 17(20)-cis pregnadien 21 oate, 14a,15e-acetonide (VIII) 7 :One part of methyl 35,115,14a,15a-tetrahydroxy-4Q7 (20) cis pregnadien-2l-oate,l4a,TSa-acetonide (VII') was dissolved in parts. of ethyl acetate and shaken with 3.5 parts of activated manganese dioxide at room temperature for about 24" hours. The mixture was filtered with the aid of 1 part of Celite and the filtrate 'concentrated to give crystalline methyl 3-ketO1l,B,14ot,l5octrihydroxy 4,17 (20)-cis-pregnadien-2 l-oate, l4a,15ix-acetonide (VIII). 1

Following the procedure of Example 11, but substituting for methyl 35,11,8,14u,1Sa-tetrahydroxy-4,l7 (20)-cis-pregnadien-21-oate,14a,15u-acetonide (VII') a corresponding compound prepared from one of the ketones set forth in the second paragraph following Example 7, yields another 1406,150t-k6t01'1ld6 of methyl 3- keto' llfi,l4cz,l5oc trihydroxy-4,l7(2Q)-cis-pregnadien- 21-oate (VIII).

Following the procedure of Example 11.but sub stituting for methyl 3 3,115,140,l5a=tetrahydroxy-4,l7 (20)-eis-pregnadien-21-oate, 14oc,15a-3.C6t0r1id6 (VII') its 6ovmethyl counterpart (VII') yields .methyl Z-keto-llfi, I4oc,15ot trihydroxy-6a-methyl-4,17(20)-cis-pregnadien- 2 1-oate, l4a,15a-acetonide (VIII).

Example 12. 3 -,l eto-?14a,15u irihydroxy-4,17(20)- W cis-pregnadien-Zf-oic acid, 14a,15a-acetonide (VIIIa) I Following the procedure of Example 4 substituting methyl it-keto l1[3,14u,15a trihydroxy-4,l7(20)=-cispregnadien-Zl-oate, 14x,l5a-acetonide (VIII) as starting material, yields 3-keto-115,14a,15a-trihydroxy-4,17

(20) -:cis pregnadiemZI-oic acid, 14oel5a-acetonide (VIIIa).

Following the procedure of Example 12 but employing material, yields 3-keto-1113,14a,15a trihydroxy-4,17 (20)-cis-pregnadien-21-oate, 14a,15a-acetonide (VIII) as starting material, yields 3-keto-11fi,14a:,15a-trihydroxy 6a-methyl-4,l7(20)-cispregnadien-2l-oic acid, :,15aacetonide (VIIIa). 1

Following the procedures of the immediately preceding paragraph and Example 12, but substituting a corresponding compound prepared from one of the ketones set forth in the second paragraph following Example 7 for the 14a,15r-acetonides (VIII) employed herein, yields another 14u,l5a-ketonide (VIIIa).

Example '13.-Methyl 3,11 diketo-14a,ISe dihydrOxy- 1,4,17(20) cis pregnatrien-21-oate,14a,ISa-acetOnide A mixture containing 10 g. of methyl 3,1l-diketo-14a, 15ot-dihydroxy-4, L7 (20 -cis-pregnadien-2 l-oate, I4OL,15OL acetonide (VII), 500 ml. of tertiary butyl alcohol, 5 m1.

of glacial acetic acid and 4 g. of selenium dioxide is warmed at reflux for a period of about 24 hours. An additional 4 g. portion of selenium dioxide is added and warming is continued for another 24-hour period. The reaction mixture is cooled and filtered. The filtrate is concentrated to about 150 ml., then slowly diluted with 850 ml. of water. The resulting precipitate is isolated by filtration. The precipitate is dissolved in 300 ml. of ethyl acetate, then washed successively with four 100 ml. portions of freshly prepared cold ammonium sulfide, dilute ammonium hydroxide, water, dilute hydrochloric acid and water. The solution is dried over sodium sulfate and evaporated to give a residue containing methyl 3,11- diketo 14a,l5oc dihydroxy-1,4,17(20)-cis-pregnatrien- 21-oate, l4a,15 x-acetonide (IX). The residue is dissolved in 50 ml. of methylene chloride and 100 ml. of Skellysolve B. The solution is then chromatographed over a column containing 400 g. of Florisil. The column is eluted with Skellysolve B. The solution is then chromatographed over a column containing 400 g. of Florisil. The column is eluted with Skellysolve B containing increasing proportions of acetone to give methyl 3,11- diketo 14a,15a dihydroxy-1,4,17(20)-cis-pregnatrien- 21-oate, 14a,15a-acetonide (IX), a light colored, crystalline solid, which can be further purified by recrystallization from acetone-Skellysolve B mixtures.

Heating methyl 3,11 diketo 14a,15a-dihydroxy-4,l7 (20)-cis-pregnadien-2l-oate, 14u,15a-acetonide (VII) in dry benzene with 2,3-dichloro-5,6-dicyanobenzoquinone under reflux for a period of about 12 hours (as in British Patent 852,847) also yields methyl 3,11-diketO-l4ot,15ot dihydroxy 1,4,17(20)-cis-pregnatrien-2l-oate, l4oz,l5ocacetonide (IX).

Following the procedures of Example 13 and the paragraph thereafter but employing methyl 3,11-diketo-14u, 15a dihydroxy 6a-methyl-4,17(20)-cis-pregnadien-21- oate, 14a,15a-acetonide (VII) as starting material, yields methyl 3,11 diketo-14a,15a-dihydroxy-6a-methyl-1,4,17 ()-cis-pregnatrien-2l-oate, 140:,15oc acetonide (IX).

Following the procedures of the immediately preceding paragraph and Example 13, but substituting a corresponding compound prepared from one of the ketones set forth in the second paragraph following Example 7 for the 14a,15a-acetonides employed herein, yields another A -14a,1Sa-ketOnide (IX).

The corresponding (1) ll-hydrogen and (2) 6a-methylll-hydrogen compounds of Formula VII prepared in the first paragraph following Example 7 can likewise be converted to their A -counterparts (IX) by following the procedures of the three immediately above paragraphs and of Example 13.

Example 14.-Methyl 3,11-diketo-14a,15u-dihydroxy-4,6, 17(20)-cis-pregnatrien-21-oate, 14u,15a-acetonide (IX) washed with dilute sodium hydroxide, water and then dried. The solvent is distilled leaving a residue (crude and crystalline) with after purification by chromatography through a Florisil column and crystallization gives methyl 3,1l-diketo-14u,15a-dihydroxy-4,6,17(20) cis-pregnatrien-Zl-oate, 14u,15u-acetonide (IX).

'Following the procedure of Example 14 but employinig methyl 3,11-diketo-14a,15a-dihydroxy-6a-methyl-4,17 (20) cis pregnadien 21-oate, 14a,15u-acetonide (VII), yields methyl 3,1l-diketo-l4a,15a-dihydroxy-6a-methyl- 4,6,17(20) cis pregnatrien 21 oate, 14a,15a-acetonide (IX).

Following the procedures of the immediately preceding paragraph and Example 14, but substituting a corresponding compound prepared from one of the ketones set forth in the second paragraph following Example 7 for the 14a,15a-acetonides employed herein, yields another A -14a,l5u-ketonide (IX).

The corresponding (1) ll-hydrogen and (2) 6a-methylll-hydrogen compounds of Formula VII prepared in the first paragraph following Example 7 can likewise be converted to their A -counterparts (IX) by following the procedures of the two immediately above paragraphs and of Example 14.

Example 15.-Methyl 3,1l-diketo-14u,15a-dihydroxy-1,4, 6,17(20)-cis-pregnatetraen-2l-oate, 14u,15a-acetonide (IX).

A mixture containing 10 g. of methyl 3,11-diketo-14a, 15 a-dihydroxy-4,6, 1 7'( 20) -cis-pre'gnatrien-2 l-oate', 14a,- 15a-acetonide (IX), 500 ml. of tertiary butyl alcohol 5 ml. of glacial acetic acid and 4 g. of selenium dioxide is warmed at reflux for 24 hours. An additional 4 g. portion of selenium dioxide is added and warming, is continued for another 24-hour period. The reaction mixture is cooled and filtered. The filtrate is concentrated to about 150 ml., then slowly diluted with 850 ml. of Water. The resulting precipitate is isolated by filtration. The precipitate is dissolved in 300 ml. of ethyl acetate, then washed with four 100 ml. portions of freshly prepared cold ammonium sulfide, dilute ammonium hydroxide, water, dilute hydrochloric acid and water. The solution is dried over sodium sulfate and evaporated to give a residue containing methyl 3,11-diketo-14u,15a-dihydroxy- 1,4,6, 17 20) -cis-pregnatetraen-2 l-oate, 14oz,15ot-aCetOnide (IX). The residue is dissolved in ml. of methylene chloride and 100 ml. of Skellysolve B hexanes. The solution is then chromatographed over a column contaim ing 400 g. of Florisil. The column is eluted with increasing proportions of acetone in Skellysolve B to give methyl 3,11 diketo 14w15a dihydroxy 1,4,6,17(2'0) cispregnatetraen-Zl-oate, 14a,15a-acetonide (IX), a crystalline solid, which can be further purified by recrystallization from acetone-Skellysolve B mixtures.

Following the procedure of Example 15 but employing methyl 3,11-diket0-14u,15u-dihydroxy-6u-methyl-4,6,

17(20)-cis-pregnatrien-2l-oate, 14a,15u-acetonide (IX) as starting material, yields methyl 3,11-diketo-14a,15u-dihydroxy 60c methyl 1,4,6,17(20) cis pregnatetraen- 21-oate, 14a,15a-acetonide (IX).

Following the procedures of the immediately preceding paragraph and Examples 15, but substituting a corresponding compound prepared from one of the ketones set forth in the second paragraph following Example 7 for the 14w15a-acetonides employed herein, yields another A -14a,15u-ketonide (IX).

The corresponding 1) ll-hydrogen and (2) Gut-methylll-hydrogen compounds of Formula VII prepared in the first paragraph following Example 7 can likewise be con.- verted to their A -counterparts (IX) by following the procedures of Example 14, the two immediately above paragraphs and of Example 15.

Example 16.Methyl 3,11-diketo-14a,15ot-dihydroxy-1,4,

6,17(20) cis pregnatetraen 21 oate, 14a,15a-acetonide (IX) A solution of 12 g. of methyl 3,l1-dlk6i0l4a,15uc-Clihydroxy 1,4,17(20) cis pregnatrien 21 oate, :,1511- acetonide (IX) and 10 g. of chloranil in 500 ml. of tertiary amyl alcohol is refluxed for a period of about 4.5 hours. The tertiary amyl alcohol is then distilled off under vacuum in a nitrogen atmosphere. The residue is dissolved in methylene chloride and then shaken with dilute sodium hydroxide. The precipitate that forms is separated by filtration through diatomaceous earth. The

1 organic phase of the filtrate is separated, washed first with dilute sodium hydroxide solution, then water and dried.

The solvent is distilled off leaving a residue of crystallinemethyl 3, 1 1-diketo-14a, u-dihydroxy-1,4,6,17 -cispregnatetraen-21-oate, 14a,15a-acetonide (IX).

Following the procedure of Example 16 but employing methyl 3,1l-diketo-14a,15u-dihydroxy-6a-methyl-1,4, 17(20)-cis-pregnatrien-21-oate, 14a,15u-acetonide (IX) as starting material, yields methyl 3,11-diketO-14oc,l5adihydroxy 6oz methyl 1,4,6,17(20) cis pre gnatetraen-21-oate, 14a,15a-acetonide (IX).

Following the procedures of the immediately preceding paragraph and Example 16, but substituting a corresponding compound prepared from one of the ketones set forth in the second paragraph following Example 7 for the 14a,15a-acetonides employed herein, yields another A -l4cc,1Sec-ketOIlid.

The corresponding (1) ll-hydrogen and (2) 6a-metlf1- yl-ll-hydrogen compounds of Formula VII prepared in the first paragraph following Example 7 can likewise be converted to their A -counterparts (IX) by following the procedures of Example 14, the two immediately above paragraphs and of Example 16.

Example 17.Methyl 3-keto-11B,14a,15a-trihydroxy- 1,4,17(20) cis-pregnatrien-Zl-oate, 14u,15 x acetonide (X) Following the procedures of Example 13 and the first paragraph thereafter, but substituting methyl 3-keto-11fl, 140:,15 a-trihydroxy-4, 1 7 20) -cis-pregnadien-21-oate, 14a, 15a-acetonide (VIII) as starting material yields methyl 3-ket0-115,14a,15a-trihydroxy 1,4,17(20) cis pregnatrien-21-oate, 14a,15a-acetonide (X).

Following the procedures of the second and third paragraphs following Example 13 but employing the corresponding llfl-hydroxy compounds (VIII) as starting materials instead of the ll-ketones (VII), yields the 11/3- hydroxy-14u,15a-ketonide, counterparts (X).

Example 18.Methyl 3-keto-l1,8,14u,15u-trihydroxy- 4,6,17(20) cis-pregnatrien-Zl-oate, 14a,l5a acetonide (X) Following the procedure of Example 14, but substituting methyl 3-keto-1 1 B, 140:, 15 a-trihydroxy-4, 17 20) -cis- 4,17(20)-cis-pregnadien-21-oate, 14u,15a-acetonide (VIII) as starting material, yields methyl 3-keto-l1B,14u,15atrihydroxy-4,6,17(20)-cis-pregnatrien 21 oate, 1411,15- acetonide (X).

Following the procedures of the first and second paragraphs following Example 14 but employing the corresponding llfi-hydroxy compound (VIII) as starting materials instead of the ll-ketones (VII), yields the 11,8-hydroxy-14a,15a-ketonide counterparts (X).

Example 19.Methyl 3-keto-11fi,14u,15a-trihydroxy- 1,4,6,17(20) cis-pregnatetraen-21 oate, 14a,15a-- acetonide (X) Following the procedure of Example 15 but substituting methyl 3-keto-11B,14a,l5a-trihydroxy-4,6,l7(20)-cispregnatrien-Zl-oate, 14u,15a-acetonide (VIII) as starting material, yields methyl 3-keto-11/3,14a,15u-trihydroxy- 1 ,4,6, 17 (20)-cis-pregnatetraen-2l-oate, 14a,15u-acetonide (X).

Following the procedures of the first and second paragraphs following Example 15 but employing the corresponding llfl-hydroxy compounds (VIII) as starting materials instead of the ll-ketones (VII), yields the 11fi-hydl'OXY-l4a,l5u-k6t0nid6 counterparts (X).

Example 20.Methyl 3-keto-l1/3,14a,15u-trihydroxy- 1,4,6,17(20) cis-pregnatetraen-Zl-oate, 14a,15,uacetonide (X) Following the procedure of Example 16 but substituting methyl 3-keto-115,140,15a-trihydroxy-1,4,17(2O)-cispregnatrien-Zl-oate, 14a,15a-acetonide (VIII) as starting material, yields methyl 3-keto-1 1,8,14a,15a-trihydroxy-1,4,

6,17(20)-cis-pregnatetraen-2l-oate, 14a,15u-acetonide (X).

Following the procedures of the first and second paragraphs following Example 16 but employing the corresponding 11,6-hydroxy compounds (VIII) as starting materials instead of the ll-ketones (VII), yields the llfl-hydroxy-14u,15a-ketonide counterparts (X).

Example 21.-Production of 21-oic acids (IXa, Xa) by hydrolysis of corresponding 21-oic acid methyl esters (IX, X)

Following the procedure of Example 4, but substituting for the starting 21-oic acid methyl ester employed therein other compounds such as:

(1) methyl 3,1l-diketo-14a,15a-dihydroxy-1,4,17(20)- cis-pregnatrien-Z l-oate, 1406,15Dt-3CC'10I1idC (IX),

(2 methyl 3,1 1-diketo-14ix,15a-dihydroxy-6u-methyl- 1,4,17(20)-cis-pregnatrien-2l-oate, 14a,15aacetonide (IX),

(3) methyl 3-keto-14a, 1 Sa-dihydroxy-IA, 17 (20 -cispregnatrien-2 l-oate, 14oc,l5a-3C6t0l1id (IX),

(4) methyl 3-keto-14a,15a-dihydroxy-6a-methyl-1,4,17

(20)-cis-pregnatrien-2l-oate, 14a,15a-acetonide (IX),

(5) methyl 3-keto-1 113,14a,l5a-trihydroxy-1,4,17(20)- cis-pregnatrien-Zl-oate, 1404,15a-Z1C6t0l1id6 (X),

(6) methyl 3 -keto-l 1,8,14u,15u-trihydroxy-6a-methyl-4,

6,17(20)-ois-pregnatrien-2l-oate, 1401,1501- acetonide (X),

(7) methyl 3,11-diketo-14a,15u-dihydroxy-4,6,17(20) cis-pregnatrien-2 l-oate, 1411,15 int-acetonide (IX),

(8) methyl 3,11 diketo-14a,1Sa-dihydroxy-6a-methyl-4,

6,17(20)-cis-pregnatrien-2l-oate, 14a,15a-ace tonide (IX),

(9) methyl 3-keto-14a,15a-dihydroxy-4,6,17 (20) -cispregnatrien-Zl-oate, 14a,15a-acetonide (IX),

( l0) methyl 3 keto-14a,15oc-dihydroxy-6wmethyl-1,4,6,

17 (20) -cis-pregnatrien-14u,1Six-acetonide (IX),

(11) methyl 3-keto-1lfi,14a,15a-trihydroxy-4,6,17(20)- cis-pregnatrien-2 l-oate, 14a,15a-acetonide (X),

( 12) methyl 3-keto-1 15,1411,15a-trihydroxy-6a-methylcis-pregnatrien-2 l-oate, 14a,1'5a-acetonide (X),

(13) methyl 3,11-diketo-14a,15a-dihydroxy-1,4,6,17(20)- cis-pregnatetraen-Zl-oate, 14a,15a-acetonide (IX),

( 14) methyl 3,11-diketo-14a,15a-dihydroxy-6a-methyl- 1,4,6,17 20) -cis-pregnatetraen-2 l-oate, 14ac,15ocacetonide (IX),

( 15) methyl 3-keto-14a,15u-dihydroxy- 1 ,4,6,17 (20 -cispregnatetraen-Z l-oate, 14a,15a-acetonide (IX),

( 16) methyl 3-keto-14a,15a-dihydroxy-6a-methyl-1,4,6,

17(20)-cis-pregnatetraen-21-oate, :,15ocacetonide (IX),

(17) methyl 3-keto-1 1 3,140,15a-trihydroxy-1,4,6,17(20)- cis-pregnatetraen-2 1 -oate, l4oc,l5a-3C6t0l1id6 (X),

(18) methyl 3-keto-1 1 [3, 14a,15 a-trihydroxy-fia-methyb 1,4,6,17(20)-cis-pregnatetraen-2l-oate, 14a,15a-aceto nide (X), etc., yields, respectively,

( 1) 3,11-diketo-14a,15u-dihydroxy-1,4,17(20)-cis-pregnatrien-2 l-oic acid, 14u,150c-3Ct01'1id6 (IXa (2) 3,1 1-diketo-14a,15a-dihydroxy-6u-methyl-1,4, 17 20 cis-pregnatrien-Zl-oic acid, 140:,15oc-21C61Z0I1id6 (IXa) (3) 3-keto-14a,15 a-dihydroxy-1,4, 17 20 )-cis-pregnatrien- 2 l-oic acid, 14a,15a-acetonide (IXa),

(4) 3-keto-14a,15a-dihydroxy-6a-methyl-1,4,17(20)-cispregnatrien-21-oic acid, 14a,15a-acetonide (IXa),

(5) 3-keto-115,140,15a-trihydroxy-1,4,l7(20)-cis-pregnatrien-Zl-oic acid, 14a,15a-acetonide (Xa) (6 3-keto-1 1[3-,14a,15a-trihydroxy-6a-methyl-,4,6, 17-

( 20 -cis-pregnatrien-2 l-oic acid, 14u,15a-acetonide (7) 3,1l-diketo-14a,15a-dihydroxy-4,6,17(20)-cis-pregnatrien-21-oic acid, 140:,15oL-E1Cfit011id6 (IXa) (8) 3,11-diketo-14u,15a-dihydroxy-6u-methyl-4,6,17-

(20)-cis-pregnatrien-21-oic acid, 14a,15a-acetonide (9) 3-keto-14u,15u-dihydroxy-4,6,17(20)-cis-pregnatrien- 21-oic acid, 14a,l5a-acetonide (IXa),

Following the procedure of Example 21 but substituting a corresponding compound prepared from one of the ketones set forth in the second paragraph following Example 7 for the l4u,15a-acetonides (IX, X) employed herein, yields another 140:,15u-k6t011id6 (IXa, Xa).

We claim:

1. Compounds of the formula wherein the 1(2)- and 6(7)-carbon atom linkages are selected from the group consisting of single bonds and double bonds; R and R are selected from the group consisting of hydrogen and methyl; Z is selected from the group consisting of the methylene radical CH2), the ,B-hydroxymethylene radical and the carbonyl radical C==O); a and b are selected from the group consisting of lower alkylwof from one through twelve carbon atoms, phenyl and benzyl.

2. A compound of claim 1 wherein the 1(2)- and 6(7)- carbon atom linkages are single bonds, R is hydrogen, R is methyl, Z is B-hydroxymethylene and a and b are methyl, namely, methyl 3-keto-l1,9,14a,15a-trihydroxy- 4,17(20)-cis-pregnadien-21-oate, 14a,15a-acetonide.

3. A compound of claim 1 whereinthe 1(2)- and 6(7)- carbon atom linkages are single bonds, R is hydrogen, R is methyl, Z is carbonyl and a and b are methyl, namely, methyl 3,1l-diketo-14a,15a-dihydroXy-4,17(20)- cis-pregnadien-Zl-oate l4a,l5u-acetonide.

4. A compound of claim 1 wherein the 1(2)- and 6(7)-carbon atom linkages are single bonds, R and R' are methyl, Z is fl-hydroxymethylene and a and b are methyl, namely, methyl 3-keto-11fi,14a,15a-trihydroxy- 6a-methyl-4,17(20)-cis-pregnadiene 21 oate, 1441,1500- acetonide.

5. A compound of claim 1 wherein the 1(2)-carbon atom linkage is a double bond, the 6(7)-carbon atom linkage is a single bond, R is hydrogen, R is methyl, Z is fi-hydroxymethylene and a and b are methyl, namely,

18 methyl 3 keto l1,8,14a,ISa-trihydroxy-1,4,17(20)-cispregnatrien-Zl-oate, 14a,15a-acetonide.

6. A compound of claim 1 wherein the 1(2)-carbon atom linkage is a single bond, the 6(7)-carbon atom linkage is a double bond, R is hydrogen, R is methyl, Z is fl-hydroxymethylene and a and b are methyl, namely, methyl 3 keto 11,9,14a,15a-trihydroxy-4,6,17(20)-cispregnatrien-Zl-oate, 14a,1'5a-acetonide.

7. A compound of claim 1 wherein the 1(2)- and 6(7)-carbon atom linkages are double bonds, R is hydrogen, R is methyl, Z is fi-hydroxymethylene and a and b are methyl, namely, methyl 3-k6tO-11fi,14a,l5a-t1ihydroxy 1,4,6,17(20)-cis-pregnatetraen-2l-oate, 1402,1501,- acetonide.

8. Acompound of claim 1 wherein the 1(2)- andv 6(7)-carbon atom linkages are single bonds, R and R are hydrogen, Z is B-hydroxymethylene and a and b are methyl, namely, 3-keto-11 3,14a,l5a-trihydroxy-4,17(20)- cis-pregnadien-Zl-oic acid, 14a,15a-'acetonide.

9. Compounds of the formula HO k 1 J 2 l HO- 7 wherein the 1(2) and 6(7)-carbon atom linkages are selected from the group consisting of single bonds and double bonds; R and R are selected from the group consisting of hydrogen and methyl; a and b are selected from the group consisting of lower alkyl of from one through twelve carbon atoms, phenyl and benzyl.

10. A compound of claim 9 wherein the 1(2)- and 6(7)-carbon atom linkages are single bonds, R is by drogen and R, a andv b are methyl, namely, methyl, 3,8,11B,14a,15a-tetrahydroxy-4,17(20) cis pregnadien- 2l-oate, 14a,15a-acetonide.

11. Compounds of the formula (IQOOR' CH CH5.

, 19 a 20 R is methyl and Z is carbonyl, namely, methyl 3,11- ofrFormul-a II with an alkylhaloformate to yield a diketo-4,14,l7(2))-cis-pregnatrien-2l-oate. corresponding compound oflthe fornaula 13. Compounds of the formula l I CH3 cm 7 1 or c an, c OR a 5 Cm (i=0 on, u or i i 1 I *7 z r --0-rJ-0R' I l a a 10 a ,7 7

/\/ E i i 5 111 l 'OH 011 O: i

y g a a wherein R, R and Z" have the same meaning as wherein Rqand R are selected from the group consisting above; V

of hydrogen and methyl and Z is selected from the group (3) Pyrolyzmg 3 thus P P correspondlPg consisting, methylene and carbonyl: pound of Formula III to yield a corresponding comi 14. A compound of claim 13 wherein R is hydrogen, pound of the formula R is methyl and Z is carbonyl, namely, methyl 3,1E-di- OH; keto-14a,15u-dihydroxy-4,17(20)-cispregnadicn-2l-oate. 7 CH3 15. A process for the production of a compound of V I claim lot the formula r a"; I

I CH:3 V 7 1 10 011' i 1 a CH 1 '7 Q i I Z a 7 i l I wherein R and Z have the same meaning as above; V (4) subjecting to Favorskii rearrangement a thus proa a b; duced corresponding compound of Formula IV to if i 1 VII yield a corresponding compound of the formula wherein R is selected from the group consisting of hya i CH3 drogen and methyl, R is lower alkyl, Z is selected from COOR I the group consisting of methylene and carbonyl and a 0 and b are selected from the group consisting of lower 7 CHi' II alkyl of from one throughtwelve carbon atoms, phenyl and benzyl, which comprises: EZ (1) fermenting a corresponding compound of the formula CH2 i ,Z V

'CH; 0 a (i=0 a ii R J a i wherein R, R and Z have the same meaning as I I above; 7' 5 i (5 oxidizing a thus produced corresponding compound of Formula V at'the 14aand 15apositions to yield I r a corresponding compound of the formula O:\/\/ i V 7 CH3 T Y COOR' R L 1 ('JH i wherein R and Z have the same 'r'neaning as above, CH3 V with a; 15a-hyd'r'oxylating microorganism to yield a corresponding compound of the formula CH3 5 I gm f e s I r 1 H' OH 1 i CH3; O t V VI I /-:-OH whereinR, R' and'Z have the same meaning as m above;

g (6) treating a thus produced corresponding compound 0: of Formuia VI with.a ketone of the formula 0 a R V I wherein R and Z have the same meaning as above; V i

(2) mixing a thus produced rcorrespogding compound V V B b 21 wherein a and b have the same meaning as above, in the presence of an acid catalyst, to yield a corresponding compound of Formula VII, above.

16. A process in accordance with claim 15 wherein the compound of Formula I is 4-pregnene-3,11,20-trione, the compound of Formula II is 15a-hyd'roxy-4-pregnene- 3,11,20-trione, the compound of Formula III is 150:- hydroxy-4-pregnene-3,11,20-trione, 15 carbonate ester, the compound of Formula IV is 4,l4-pregnadiene-3,11,20- trione, the compound of'Formula V is methyl 3,1l-diketo- 4,14,l7(20)-cis-pregnatrien-21 oate, the compound of Formula VI is methyl 3,11-diketo-l4a,15a-dihydroxy 4,17(20)-cis-pregnadien-2l-oate and the compound of Formula VII is methyl 3,1l-diketo-14a,15u-dihydroxy- 4,l7(20)-cis-pregnadien-21-oate, 14a,15a-acetonide.

17. A process for the production of a compound of claim 1 of the formula COOR' H 5 1 l I /s g o 0 o: o

i 8 b R VII wherein R is selected from the group consisting of hydrogen and methyl, R is lower alkyl, Z is selected from the group consisting of methylene and carbonyl and a and b are selected from the group consisting of alkyl 'of from one through twelve carbon atoms, phenyl and benzyl, which comprises:

(1) subjecting to Favorskii rearrangement of a correwherein R and Z have the same meaning as above, to yield a corresponding compound of the formula 100m CH on,

wherein R, R and Z have the same meaning as above;

(2) oxidizing a thus produced corresponding compound of Formula V at the l4ozand 15uposi- 22 tions to yield a corresponding compound of the formula COOR CH3 ll on ()H VI R wherein R, R' and Z have the same meaning as above; (3) treating a thus produced corresponding compound of Formula VI with a ketone of the formula COOR' wherein R is selected from the group consisting of hydrogen and methyl, R is lower alkyl, Z is selected from the group consisting of methylene and carbonyl and a and b are selected from the group consisting of lower alkyl of from one through twelve carbon atoms, phenyl and benzyl, which comprises:

(l) oxidizing a corresponding compound of the formula C O O R CH CH3 H it v wherein R, R and Z have the same meaning as 23 above, to yield a corresponding compound of the formula wherein R, R and Z have the same meaning as above;

(2) treating a thus produced corresponding compound of Formula VI with a ketone of the formula wherein a and b have the same meaning as above, in the presence of an acid catalyst to yield a corresponding compound of Formula VII, above.

20. A process in accordance with claim 19 wherein the compound of Formula V is methyl 3,11 diketo- 4,14,17(20)-cis-pregnatrien-2l-oate, the compound of Formula VI is methyl 3,11 diketo-l4u,l5a-dihydroxy- 4,14,17(20)-cis-pregnatrien 21 oate, the compound of Formula VI is methyl 3,11 diketo-14u,l5a-dihydroxy- 4,17(20)-cis-pregnadien-21-oate, l4a,15a-acetonide.

, 21. A process for the production of a compound of claim 1 of the formula COOR CH CH: H

R VII wherein R is selected from the group consisting of hydrogen and methyl, R is lower alkyl, Z is selected from the group consisting of methylene and carbonyl and a and b are selected from the group consisting of lower alkyl of from ofne through twelve carbon atoms, phenyl and benzyl, which comprises; treating a corresponding compound of the formula wherein R, R' and Z have the same meaning as above, with a ketone of the formula VIII wherein R is selected from the group consisting of hydrogen and methyl, R is lower alkyl and a and b are selected from the group consisting of alkyl of from one through twelve carbon atoms, phenyl and benzyl, which com-prises;

(l) reducing at the 3- and 11- positions a correspond ing compound of the formula VII wherein R, R, a and b have the same meaning as above, to yield a corresponding compound of the formula COOR' l I o l t I g wherein R, R, a and b have the same meaning as above;

(2) oxidizing a thus produced corresponding compound VII of Formula VII at the 3fi-position to yield a corre- References Cited sponding compound of Formula VIII, above. UNITED STATES PATENTS 24. A process in accordance with claim 23 wherein the compound of Formula VII is methyl 3,11-diketo- 3147 248 9/1964 Beal et a1 260-23955 14a,15a-dihydr0xy-417(20)-cis-prenadien 21 oate, 14a,15u-acetonide, the compound 0f Formula VII is 5 ELBERTL' ROBERTS Pnmary Exammer methyl 3,8,11;3,14a,15a-tetrahydroxy 4,17(20) cis ETHEL G. LOVE, Assistant Examiner pregnadien-Zl-oate, 14a,15a-acetonide and the compound of Formula VIII is methyl 3-ket0-11B,14a,15a-trihydroxy- US. Cl. X.R.

4,l7(20)-cis-pregnadien-21-0ate, 14a,15x-acetonide. 1O ;2 0 97 3973 3974 399 45 999 PAGE TWO UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,502,659 Dat d March 24. 1970 Inventm-(s) Philip F. Bea] Ill and Robert W. Jackson It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 19, line 45, for read 8K SEPB-IQYO (SEAL) Amen.

mm 3. sum, .13.

comissiom 01' Paul!" Meeting Officer FORM USCOMM-DC 60376-P69 U 5 GOVERNMENT PRINTING OFFICE I 1.. O-lI-QQ 

